Sympathetic Ophthalmia

Sympathetic ophthalmia (SO) is a rare, bilateral, nonnecrotizing, granulomatous uveitis that occurs after ocular trauma or surgical procedures to one eye threatening sight in the fellow eye. The pathophysiology is not clearly understood, but it appears that the disrupted integrity of the inciting eye leads to an autoimmune reaction against the exposed ocular antigens in the injured eye as well as in the sympathizing eye.


Sympathetic Ophthalmia Sympathetic Ophthalmia
Sympathetic ophthalmia (SO) is a rare, bilateral, nonnecrotizing, granulomatous uveitis that occurs after ocular trauma or surgical procedures to one eye threatening sight in the fellow eye. The pathophysiology is not clearly understood, but it appears that the disrupted integrity of the inciting eye leads to an autoimmune reaction against the exposed ocular antigens in the injured eye as well as in the sympathizing eye.
With the aid of our full colour graphics this discussion aims to explain the pathophysiology behind sympathetic ophthalmia including an essential discussion of the immune tolerance mechanisms, which render the eye an immune privileged organ.

Antigen exposure and tissue injury Antigen exposure and tissue injury
Ocular antigens are normally sequestered within the eye behind the blood-retinal barrier, thus preventing exposure of these antigens and their detection by the systemic immune system. However, in the event of a penetrating injury or surgical procedure this barrier is breached and ocular antigens leak into the systemic environment. The tissue damage alerts and recruits antigen presenting cells, such dendritic cells, to the site where they phagocytose and process the free ocular antigens into peptide fragments. CD4+ helper T cells recognize the peptides presented by class II [simple_tooltip content=' HLA is Human Leukocyte Antigen which is part of the Major Histocompatibility Complex (MHC) which are a set of genes that, in part, direct T cell mediated immunity. There are two classes of MHC that are involved with directing T cell immunity: class I present peptides to CD8+ T cells and class II present peptides to CD4+ T cells. The peptides presented by either classes of MHC are derived from either "self" (own proteins) or from invading pathogens. HLA are one of the most polymorphic genes, meaning that many variants exist and the pairs of inherited genes create a unique set of immune responses in each person. HLA are known to be associated with different diseases and with transplantation compatibility/ incompatibility. ']HLA[/simple_tooltip] in distal secondary lymphoid structures, such as lymph nodes or the spleen.
Under normal circumstances, where ocular antigens remain in the eye, CD4+ helper T cells do not recognise ocular proteins because autoreactive T cells are deleted in the thymus during T cell development. However, there are rare instances when an autoreactive T cell develops because there is cross-reactivity between the ocular peptide and a previously encountered peptide, which may have occurred in response to previous immune responses to other infections. This crossreactivity with a peptide seen previously in an infection is known as molecular mimicry. When this occurs T cells that respond to the ocular antigen undergo clonal expansion and migrate to the site of inflammation.
Under normal circumstances, where ocular antigens remain in the eye, CD4+ helper T cells do not recognise ocular proteins because autoreactive T cells are deleted in the thymus during T cell development. However, there are rare instances when an autoreactive T cell develops because there is cross-reactivity between the ocular peptide and a previously encountered peptide, which may have occurred in response to previous immune responses to other infections. This cross-reactivity with a peptide seen previously in an infection is known as molecular mimicry. When this occurs T cells that respond to the ocular antigen undergo clonal expansion and migrate to the site of inflammation.
Activated T cells up-regulate surface receptors that allow them to extravasate from the blood circulation into inflamed tissue. Vascular endothelial cells also upregulate receptors to facilitate this process when stimulated by inflammatory cytokines such as [simple_tooltip content=' Interleukin 1(IL-1) has many functions on many different cells and is secreted by a number of cells including macrophages, monocytes and dendritic cells. It also helps to activate T helper cells by acting as a co-stimulator with the antigen presenting cell receptors and it helps promote the maturation and clonal expansion of B cells.
']IL-1[/simple_tooltip] and TNF-a. In this way ocular antigen-specific CD4+ helper T cells are able to penetrate the usually impervious blood-retinal barrier in the damaged eye and respond to the same ocular antigens. The inflammatory response continues to recruit more immune cells overwhelming the immune privilege status of the eye and causing further damage. This continues if unchecked, resulting in the swelling observed in our case, unless immunosuppressive drug therapy is initiated.

Inflammation in the sympathising eye Inflammation in the sympathising eye
In our related case study, the patient returned 3 weeks later with orbital swelling in the right "sympathising" eye. This is most likely due to systemic cytokine effects, with CD4+ helper T cells specific for the ocular antigen originally from the damaged left eye, which can now penetrate the blood-retinal barrier of the undamaged right eye (sympathizing eye). This initiates an immune response to the same antigen. Penetration of the right eye is likely due to upregulation of receptors on vascular endothelial cells in the sympathising eye by the action of IL-1 and TNF-a. The activated T cells secrete cytokines that recruit further T cells and antigen presenting cells that can continue to process ocular antigens. This cycle of events leads to inflammation and subsequent damage to the sympathising eye that can cause visual loss unless the damaged eye is removed early enough or immunosuppressive drugs are initiated in time.
Lets look at the pathophysiology of sympathetic ophthalmia in closer detail, as this is an example of how immune tolerance is broken which causes disruption to an immune privileged organ.
The eye is an essential organ of survival because it provides vision. For this reason it is one of the body's immune privileged sites and mechanisms of immune tolerance operate to protect ocular tissues from immune-mediated damage. Other areas of the body which display similar immune tolerance include the brain, placenta and testis.
Ocular tissues have minimal ability to regenerate if damaged and therefore regulatory systems are in place to limit excessive pro-inflammatory immune responses. These include simple barrier systems to restrict antigen and cellular traffic as well as soluble and cell-bound factors that suppress immune cell activation. Six such mechanisms are discussed here in more detail: a) blood-retinal barrier; b) immune evasion; c) apoptosis; d) inhibitory factors; e) soluble immunosuppressive factors and f) immune deviation.

The Blood-retinal Barrier The Blood-retinal Barrier
Segregation of antigens from immune cells in the periphery is partially achieved by the blood-retinal barrier. Vascular endothelial cells are connected by impermeable tight-junctions and there is a basement membrane (Bruch's membrane) that prevents soluble molecules from diffusing out of the eye. The retinal pigment epithelium is also an impermeable cell layer connected by tight junctions to protect the photoreceptor cells. The eye also lacks a lymphatic system, which serves as a drainage for inflammatory agents, and so the effects of inflammation are highly constrained. However, the important point to note, is that ocular antigens can prime new T cell responses at lymph nodes distal to the eye. In our case, the patient developed a cervical [simple_tooltip content='An abnormal enlargement of the lymph nodes, usually associated with pathology.
']lymphadenopathy[/simple_tooltip] at the time of the sympathizing eye becoming inflamed.

Immune Evasion Immune Evasion
The primary goal of immunosuppressive mechanisms in the eye is to circumvent damage to cells required to maintain vision. Mechanisms known to operate in the protection of ocular tissues from attack by cytotoxic immune cells such as natural killer cells and CD8+ cytotoxic T cells involve lack of expression of the classical class I [simple_tooltip content='HLA is Human Leukocyte Antigen which is part of the Major Histocompatibility Complex (MHC) which are a set of genes that, in part, direct T cell mediated immunity. There are two classes of MHC that are involved with directing T cell immunity: class I present peptides to CD8+ T cells and class II present peptides to CD4+ T cells. The peptides presented by either classes of MHC are derived from either self (own proteins) or from invading pathogens. HLA are one of the most polymorphic genes, meaning that many variants exist and the pairs of inherited genes create a unique set of immune responses in each person. HLA are known to be associated with different diseases and with transplantation compatibility/ incompatibility. ']HLA[/simple_tooltip] A, B and C molecules and the expression of non-classical class I HLA E and G receptors. Specifically it has been shown that the absence of HLA A, B and C receptors prevents CD8+ cytotoxic T cells from responding to foreign peptides while the expression of HLA E and G receptors interacts with CD94/NKG2 receptors inhibiting the action of natural killer cells.

Apoptotic Factors and Inhibitory Factors Apoptotic Factors and Inhibitory Factors
The cells of certain ocular tissues express membrane receptors that induce apoptosis or inhibition of activated immune cells as well as cellular enzymes that deplete tryptophan, an [simple_tooltip content=' Any organic acid containing one or more amino groups (NH2) and a carboxyl group (CO2H) forming the essential components of proteins.
']amino acid[/simple_tooltip] essential for T cell survival. Several of these mechanisms are now well understood. For simplicity, our graphic has been divided into two: one part which describes the factors involved in apoptosis and the second part which describes the inhibitory factors. Although depicted separately these are processes which occur simultaneously. FasL and PD-L1 engagement promotes apoptosis in activated T cells following interaction with respective Fas and PD-1 receptors. While another ligand, TRAIL (TNF-related apoptosis ligand), engages with receptors on macrophages and neutrophils to induce apoptosis. Activated neutrophils also express Fas that interacts with FasL to promote apoptosis. CD86 receptors engage with the inhibitory receptor CTLA-4 on T cells. In addition, some ocular cells inhibit T cell proliferation by mediating depletion of tryptophan with IDO (indolamine 2,3-dioxygenase).

Soluble Immunosuppressive Factors Soluble Immunosuppressive Factors
Other immunosupressive mechanisms in the eye include secretion of soluble factors into the aqueous and vitreous humor. Some of these factors are seen in the other immune privilege sites.
TGF-beta is a potent suppressor of activation of T cells, natural killer cells and macrophages. It also primes antigen presenting cells to preferentially generate regulatory T cells in response to antigen presentation. CGRP and a-MSH prevent activated macrophages from secreting pro-inflammatory cytokines. VIP suppresses T cell activation SOM prevents activated T cells from secreting IFN-gamma. Neutrophils do not become activated under the action of sFasL. MIF inhibits natural killer cell cytotoxic function. CRP prevents activation of the complement cascade.

Immune Deviation Immune Deviation
This process is a mechanism that protects the eye from collateral damage to an immune-mediated damaging response after infection. In a normal situation, when foreign antigens are deposited in the anterior chamber, due to infection, pro-inflammatory immune responses fail to be elicited due to anterior chamber-associated immune deviation (ACAID). Although this has only been described in experimental models, it is thought that ocular antigen presenting cells can preferentially select and